Biodegradable polymers are being used for many applications in medicine, including as a carrier for controlled release drug delivery systems, and in biodegradable bone pins, screws, and scaffolds for cells in tissue engineering. A principal advantage of the materials based on biodegradable polymers over existing non-biodegradable polymers or metal-based material is that the products are removed over time by bioerosion, avoiding the need for surgical removal.
Despite the growing need in medical applications, only few synthetic biodegradable polymers are currently used routinely in humans as carriers for drug delivery: ester copolymers of lactide, lactone and glycolide (PLA family) and anhydride copolymers of sebacic acid (SA) and 1,3-bis-carboxyphenoxy)propane (CPP). PLA is the most widely used due to its history of safe use as surgical sutures and in current drug delivery products like the Lupron Depot 19. While the development of PLA remains among the most important advances in medical biomaterials, there are some limitations that significantly curtail its use, in particular:
1. PLA polymers typically take a few weeks to several months to completely degrade in the body, but the device is typically depleted of drug more rapidly.
2. PLA devices undergo bulk erosion, which leads to a variety of undesirable outcomes, including exposure of unreleased drug to a highly acidic environment.
3. It is difficult to release drugs in a continuous manner from PLA particles owing to the polymers' bulk-erosion mechanism.
4. The particularly fine PLA particles needed for intravenous injection or inhalation can agglomerate significantly, making resuspension for injection or aerosolization for inhalation difficult.
Polyanhydrides, because of their more labile polymer bond, show a more rapid degradation rate and also tend to exhibit surface, rather than bulk degradation. Because of these advantages, polyanhydrides polymers may be preferred in biological applications where it is critical to achieve a high degradation rate and/or a better controlled rate of erosion from the polymer surface.
More recently, mixed polester/polyanhydride polymers that combine the release characteristics of both polyester and polyanhydride polymers have been proposed. See, for example, Storey, R. et al., J. Macromol Sci., Pure Appl. Chem., A34(2) pp 265-280 (1997), U.S. Pat. No. 5,756,652, and Korhonen, H. et al., Macromol Chem. Phys., 205, pp 937-945 (2004). These polymers may be thought of as containing a selected proportion of ester and anhydride linkages along the polymer backbone chains. Increasing the proportion of anhydride linkages in the mixed polymers leads to enhanced rate of surface erosion. In certain types of mixed polyester/polyanhydride polymers, at least, the rate of erosion was found to be biphasic, evidencing a relatively rapid release of polyester components and a slower breakdown of the released polyester moieties.
One limitation of polyanhydride polymers, however, is their relatively high stiffness, or Young's modulus of elasticity, typically in the range of 3-5 GPa, making these polymers unsuitable for applications in which polymer expansion or bending is required. One important area where an expandable polymer would be useful is intravascular stents, which are carried on balloon catheters and deployed at a site of vascular injury by radial expansion, requiring the ability to expand significantly, and once expanded to hold their shape within a vessel. These physical requirements have limited stent construction heretofore largely to metal-lattice construction.
It would thus be desirable to provide a biocompatible, biodegradable polymer having improved biodegradation and drug-release properties. It would also be desirable to provide a biocompatible, biodegradable stent having the requisite deformability and shape-retention, but also capable of biodegrading over a desired “stenting” period and exhibiting surface rather than bulk erosion.